Microcapsules and Microspheres formed from various natural and synthetic polymers and resins have become popular delivery vehicles for various active agents such as drugs, diagnostic reagents and the like. Degradable microcapsules and microspheres are of particular interest for use in so called xe2x80x9cdepotxe2x80x9d formulations, where delivery of the active agent over an extended period of time is desired. Despite the growing number of uses of microcapsules and microspheres, there remains a need for an economic, safe and reliable method for their manufacture and formulation that avoids the most significant wastes and expenses associated with existing methods, while simultaneously enabling the ability to aseptically formulate the products in a simple and efficient manner.
Processes for preparing microcapsules and microspheres typically involve the formation of at least one dispersed phase in a continuous phase. The dispersed phase typically includes the active agent. In the case of microspheres, the dispersed phase will also typically include polymer so that, upon solidification in the continuous phase, the dispersed phase becomes a microsphere. Microcapsules are similarly formed using multiple phases. In a typical practice, a water-oil-water (w/o/w) emulsion is formed, and the polymer caused to precipitate out of one phase onto the surface of a dispersed phase to form a capsule wall thereon upon solidification of the polymer. Once the capsules or spheres are produced, they must then be formulated into a finished dosage form.
Most microsphere processes result in a suspension of particles in a suspending liquid that is not the suspending liquid desired for the final dosage form. Current techniques for processing and formulating microspheres and microcapsules into the final dosage form typically involve dead end filtration and powder filling processes. Although the powder processes can be made aseptic, they tend to have the drawbacks of using large volumes of flammable solvents, capital intensive equipment trains are generally required for a fixed scale and they take a comparatively long time to produce a finished batch. Likewise, the time and capital expense associated with powder filling processes can put one at a significant competitive disadvantage.
There is a need for a process that can efficiently, economically and aseptically process and formulate microcapsules and microspheres into final dosage forms.
The present invention is directed to a method and apparatus for processing and formulating active agent containing polymer bodies, and more particularly microspheres and microcapsules. The method and apparatus according to the invention are ideal for formulating microcapsules and microspheres suitable for carrying drugs, diagnostic reagents, or various other active agents into final dosage form. The inventive method provides a simple, economic, efficient and aseptic means of formulating a product wherein the sterile field need not be compromised throughout the entire production cycle. As used herein, terms such as xe2x80x9csterilexe2x80x9d and xe2x80x9casepticxe2x80x9d are taken to mean sterile or aseptic enough to meet current USP standards. The apparatus according to the invention is relatively inexpensive and easily broken down and sterilized, thereby significantly reducing capital expenditures associated with aseptic powder processes. Moreover, product batches can be produced with shorter cycle times than current processes for producing microcapsules and microspheres. A 500 gram bacth of leuprolide containing microspheres can be prepared and processed into final dosage vials on the order of three days.
The method and apparatus of the invention are most preferably employed to formulate microspheres produced in accordance with the process disclosed in co-pending application Ser. No. 08/800,924, filed Feb. 13, 1997 U.S. Pat. No. 5,945,126, incorporated herein by reference. Preferably, the active agent is a drug or diagnostic agent and the microspheres are intended for the delivery of such drug or diagnostic agent to a patient in need thereof. The preferred drugs may be peptide drugs, proteinaceous drugs, steroidal drugs, non-steroidal drugs, simple compounds and so on. A representative list of suitable drugs and other active agents may be found in U.S. Pat. Nos. 5,407,609, 4,767,628, 3,773,919 and 3,755,558, all incorporated herein by reference. Of particular interest are LH-RH agonists such as leuprolide, triptorelin, goserelin, nafarelin, historelin and buserelin, LH-RH antagonists, somatostatin and its analogs such as octreotide, human, salmon and eel calcitonin, growth hormones, growth hormone releasing hormones, growth hormone releasing peptide, parathyroid hormones and related peptides, interferon, erythropoietin, GM-CSF, G-CSF, thymosin, antitrypsin, enterostatin, and chemotherapy drugs, antibiotics and analgesics for regional administration. An especially preferred drug for use in the instant invention is leuprolide.
The advantages of the invention are accomplished by maintaining and processing the microspheres or microcapsules as a suspension. While significant advantages can be achieved by processing the product as a suspension, there is also a significant potential for product losses if adequate precautions are not taken to maintain the suspension and ensure proper product flow throughout the process.
Generally speaking, the formulating process of the invention involves the concentration, washing and. formulating of agent containing polymer bodies, i.e., microspheres or microcapsules, that are maintained in a suspension of a continuous phase. Typically, the continuous phase containing the polymer bodies is initially water, or water containing residual impurities from the process used to make the microspheres or microcapsules, such as surfactants, residual solvent and the like. In order to formulate the polymer bodies into a final product it is necessary to process the polymer bodies into an appropriate sterile concentration of polymer bodies in a suitable pharmaceutically acceptable diluent or carrier, i.e., formulating medium. The present process accomplishes this aseptically by processing the polymer bodies as a suspension using a filter capable of removing the continuous phase without deleteriously effecting the suspension of polymer bodies. The continuous phase which, as noted, can initially be water, but subsequently during the process can be other suspending media, including water for injection and formulating medium, is then cycled back to a process vessel as a suspension for further processing in subsequent phases. Advantageously, a hollow fiber filter provides an ideal means of accomplishing the concentration of the polymer bodies, and the replacement of the continuous phase with other continuous phases such as water and/or formulating medium.
In practicing the inventive method of formulating according to the invention, a suspension of agent containing polymer bodies in a continuous phase is provided in a process vessel. In a preferred embodiment the apparatus will employ only a single processing vessel, which serves to formulate the microspheres and microcapsules in accordance with the method described herein. However, configurations can be devised in which the process vessel performs multiple functions. For example, it can also serve as a solvent removal vessel as a preliminary step to the practice of the inventive method. Similarly, multiple process vessels can be employed in series, each functioning to perform one or more phases of the formulating process, such as a concentrating phase, a washing phase and a formulating phase, respectively.
Since one of the advantages of the invention is derived from the simplicity and limited capital costs of the apparatus used, it is generally preferred that a minimum number of vessels be employed. However, on larger scale processes, where significant volumes are to be processed, it may be necessary to employ two process vessels and hollow fiber filters in series to minimize losses. Thus, in another preferred embodiment, the first process vessel serves as a solvent removal vessel, into which a relatively large volume of formed or forming microspheres are directly transferred from a means for forming them, such as an in-line mixer, and also serves to perform a concentrating and washing phase. In order to minimize losses, a second process vessel and hollow fiber filter are employed to further reduce the volume and increase concentration, and also to perform the formulating phase.
While maintaining said polymer bodies in suspension in the process vessel, such as by magnetic stirrer, impeller, recirculation apparatus and the like, the continuous phase is replaced with a formulating medium by moving the suspension through the filter apparatus. Preferably, the suspension is circulated through the filter and back to the processing vessel, rather than to down stream vessels. Conceptually, any filter that is adapted to eliminate continuous phase and return the polymer bodies as a suspension to a process vessel will suffice for the practice of the invention, with the noted hollow fiber filter being preferred. As noted, the continuous phase will typically initially be water containing not only the polymer bodies, but also various impurities from the microsphere/microcapsule preparation process. Thus, while, depending upon the nature of the active agent and end use to which the product will be put it is possible to replace. the initial continuous phase directly with formulating medium, the process according to the invention will preferably include a washing phase. Likewise, since the concentration of polymer bodies in the initial continuous phase will generally be significantly less than the concentration required for the final product, the process will also preferably include a concentrating phase, in which the suspension is run through the filter to eliminate continuous phase. Once the suitable concentration of polymer bodies in the formulating medium is obtained, as ascertained by sampling and assaying the suspension from the processing vessel, the suspension of agent containing polymer bodies and formulating medium is removed from the process vessel for subsequent processing, such as filling into final product vessels.
The invention is also embodied in a novel and advantageous apparatus for formulating the agent containing polymer bodies. In particular, the apparatus employs a process vessel that is adapted to maintain a suspension of polymer bodies in a continuous phase that is coupled to the noted filter in a manner that enables the suspension to be processed through the filter so as to eliminate continuous phase, and thereafter return the suspension to the process vessel, or one or more additional process vessels, for further processing. To accomplish the further processing, the apparatus includes a source of formulating medium and, when a washing phase is employed, as source of wash water. The inventive apparatus thereby enables the microspheres or microcapsules to be processed as a suspension. Advantageously, the apparatus is relatively simple and inexpensive, and highly conducive to processing the polymer bodies aseptically.
As will be apparent, in its simplest configuration the apparatus will employ a single process vessel and filter combination that is coupled to a source of microspheres or microcapsules, as well as the water source and formulating medium source. However, it is likewise possible for a. plurality of filters and process vessels to be coupled in series, so that the output from a first processing vessel and filter can be transferred to a second process vessel and filter for, e.g., a washing step, which output may then be transferred to yet a third process vessel and filter for substitution of water from the washing step with formulating medium. Likewise, the separate vessels could all utilize the same filter. Other configurations will also be apparent to those of ordinary skill in the art in view of the instant disclosure.
As noted, many of the advantages of the present invention are derived from the ability of the apparatus to process the microspheres as a suspension. Thus, the preferred apparatus of the invention is configured using simple elastomeric tubing, peristaltic pumps and pinch clamps or similar devices. Such components not only advantageously add to the low costs associated with the invention, they enable the maintenance of the suspension by eliminating settling points and other areas where potentially significant losses can occur, such as mechanical valves, sharp turns, elbows and the like. The various components of the system are thus coupled in a manner that maximizes the ability of the system to maintain the polymer bodies in suspension. It is to be understood that the term xe2x80x9ccoupledxe2x80x9d as used herein means that the various components are operatively coupled so that the contents of one element can move to another element, but can include intermediate elements and components.
In another aspect of the invention there is provided a method of making and formulating agent containing polymer bodies. The polymer bodies are formed by forming a dispersed phase comprising an active agent, and providing a continuous phase in which the dispersed phase will form an emulsion, at least one of the dispersed and continuous phases comprising polymer. The dispersed and continuous phases are introduced into a reactor vessel that includes means for forming an emulsion, and an emulsion of the dispersed phase in the continuous phase is formed causing the polymer to form microspheres or microcapsules containing the active agent. Likewise, a series of reactors may be used to form a double emulsion for forming microcapsules. Thereafter, the said emulsion is transported from the reactor vessel to a solvent removal vessel and solvent is removed therein. Once the desired level of solvent removal is obtained, the polymer bodies are formulated by maintaining them in suspension in accordance with the aforementioned formulating process. In a preferred embodiment, the means for forming an emulsion is an in-line mixer. In another aspect of the invention, the means for forming an emulsion is a static mixer.
Many additional features, advantages and a fuller understanding of the invention will be had from the following detailed description of the preferred embodiments and accompanying drawing.